The goal of our proposed study is to determine the mechanisms underlying structural chromosome abnormalities and genomic amplification in human tumors. Genomic (gene) amplification is one of the key drivers of tumor development and progression. There are several, recurrently amplified oncogene loci in the genome. Enormous efforts have been directed to antagonizing the outcomes of oncogene amplification, such as overexpressed proteins and downstream signaling pathways. So far, little attention has been paid to the translational potential of the underlying amplification mechanisms. Our long-term goal is to translate the knowledge from genomic amplification mechanisms for controlling aggressive tumors. A genomic segment harboring an oncogene can accumulate either within chromosomes or extrachromosomally in the form of circular minichromosomes. Therefore, identifying a single molecular process for controlling genomic amplification appears challenging. We have shown that a defect in DNA replication is a crucial initiating event for genomic amplification. To faithfully duplicate the large human genome, replication machinery (forks) must travel a long distance and overcome a number of natural obstacles, such as DNA secondary structures and collisions with transcription machinery. Tumor cells and pre-cancerous lesions often fail to protect replication forks at these obstacles, and as a result, forks stall and collapse (replication stress). Collapsed forks become broken forks with recombinogenic DNA ends, which can lead to chromosomal abnormalities and genomic amplification. Although we now recognize the crucial role of replication stress, molecular mechanisms from stalled/collapsed forks to recurrent genomic amplification remain elusive. Such information is essential to identify new targets to control genomic amplification. For recurrent genomic amplification to occur, there must be a natural obstacle near an oncogene that repeatedly impedes replication fork movements. We hypothesize that locus-specific, natural genomic stress impedes replication fork movements and escorts collapsed forks into recurrent genomic amplification. We have identified candidate obstacles in two recurrently-amplified genomic loci, 8q24 with MYC oncogene (AIM1) and 17q12-21 with ERBB2 oncogene (AIM2), and will investigate molecular mechanisms step-by-step from stalled/collapsed forks to genomic amplification. Our results will reveal a specific interaction between amplification mechanisms and local genomic context, which may provide us a novel mechanistic insight with therapeutic potential.
Our long-term goal is to control aggressive tumors by elucidating oncogene amplification mechanisms. Results from our project may reveal that oncogene amplification is driven not only by a growth advantage conferred from activated oncogenes but also by a specific interaction between local genomic context and an amplification mechanism. Such results will provide a novel direction in cancer susceptibility research and previously undefined therapeutic targets against aggressive tumors.
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|Marotta, Michael; Chen, Xiongfong; Watanabe, Takaaki et al. (2013) Homology-mediated end-capping as a primary step of sister chromatid fusion in the breakage-fusion-bridge cycles. Nucleic Acids Res 41:9732-40|
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|Marotta, Michael; Piontkivska, Helen; Tanaka, Hisashi (2012) Molecular trajectories leading to the alternative fates of duplicate genes. PLoS One 7:e38958|